Data from many laboratories suggest that autoimmunity results from an imbalance in normal immunoregulation. Jerne first hypothesized that immunological reactivity was regulated by an intricate network involving idiotype-antiidiotype (id-antiid) interactions. If autoantibody production is normally regulated by a network of id-antiid interactions, then autoimmunity may result from an alteration in that network. We propose to examine the network theory in the clinically-relevant antierythrocyte antibody (aRBC) autoimmune disease of NZB mice. This autoantibody response provides a unique opportunity to dissect the id-antiid network in autoimmunity, since it is an oligoclonal response, organ specific and easily measured. We have produced a large panel of monoclonal NZB aRBC antibodies. The specific aims of the proposal are to use oour established monoclonal aRBC and monoclonal antiid antibodies to determine whether: 1) the production of aRBC in NZB mice is associated with an alteration in anti-idiotypic immunoregulation; 2) the immune network can be perturbed to the benefit of the NZB mouse by administration of antiid antibodies directed against the ids present on NZB aRBC, with subsequent specific down-regulation of id expression and remission of the autoimmune disease; 3) initial down-regulation is followed by recurrence of disease due to the appearance of escape ids, anti-antiid (Ab3) antibodies or id-antiid immune complex renal disease; and 4) recurrence, if it occurs, can be prevented by altering the type or dose of antiid antibody administered, or the combined use of antiid antibodies and cytotoxic drugs. If the administration of antiid antibodies to NZB mice results in the down-regulation of id expression and amelioration of autoimmune hemolytic disease, this research will have major implications relative to the understanding of the underlying immune defects in NZB mice and provide a model for the treatment of autoimmune disease in man, an approach which offers the possibility of highly specific immunosuppression of pathogenic autoantibody production.